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Atherosclerosis, a chronic inflammatory condition characterized by the buildup of fatty deposits (plaque) within the arterial walls, is a leading cause of cardiovascular diseases (CVD), including heart attacks, strokes, and peripheral artery disease. While the focus has traditionally been on the progression and stabilization of atherosclerotic plaques, emerging research suggests that angiogenesis, the process of new blood vessel formation, plays a pivotal role in atherosclerosis. However, this phenomenon is a double-edged sword it can be both beneficial and harmful depending on the context. While angiogenesis can support tissue repair and ischemic areas by improving blood supply, it can also exacerbate plaque instability and promote the progression of the disease [1].

Description

Angiogenesis in atherosclerotic lesions

In response to hypoxia (lack of oxygen) and inflammation, endothelial cells in the arterial walls can initiate angiogenesis. In the context of atherosclerosis, angiogenesis is often triggered by the increasing demand for oxygen and nutrients in growing plaques. As these plaques enlarge, they can outgrow their existing blood supply, leading to the formation of new, often dysfunctional blood vessels within the plaque. This process is driven by factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and other pro-angiogenic molecules [2].

While angiogenesis within plaques may seem beneficial at first glance by improving the oxygen and nutrient supply, it often leads to the development of fragile, leaky vessels. These vessels are prone to rupture, which can result in the release of pro-thrombotic materials from the plaque. The rupture of these new blood vessels or the plaques themselves is one of the key events leading to the acute clinical manifestation of atherosclerosis, such as heart attacks and strokes.

The dual nature of angiogenesis

The dual nature of angiogenesis in atherosclerosis lies in its role in both plaque progression and plaque stability. On one hand, angiogenesis is a compensatory mechanism in ischemic tissues, potentially improving oxygenation and healing [3]. In early-stage plaques or in areas where blood flow is compromised due to arterial narrowing, angiogenesis could aid in restoring sufficient blood supply to prevent further tissue damage.

On the other hand, the new blood vessels formed within the plaques are often poorly organized and prone to leakage and rupture. These vessels, by supplying the plaque with more inflammatory cells, can promote further plaque growth and destabilization. This makes angiogenesis in atherosclerosis a critical factor in the transition from stable, non-threatening plaques to unstable, rupture-prone plaques that are more likely to lead to thrombus formation, vascular occlusion, and acute cardiovascular events [4].

Molecular and cellular mechanisms

The key molecular players in angiogenesis within atherosclerotic plaques include VEGF, FGF, and angiopoietins, all of which are upregulated in response to hypoxic conditions within the plaque. These growth factors stimulate endothelial cell proliferation, migration, and the formation of new capillaries [5]. Inflammatory cells such as macrophages and T-cells also contribute to the angiogenic process by secreting pro-inflammatory cytokines that further promote angiogenesis.

Interestingly, the role of matrix metalloproteinases (MMPs) cannot be overlooked in this context. MMPs are enzymes that degrade the extracellular matrix and are involved in both the remodeling of blood vessels and the destabilization of atherosclerotic plaques. The balance between pro-angiogenic and anti-angiogenic factors is crucial in determining whether angiogenesis promotes plaque stability or instability.

Therapeutic implications

Given the complex role of angiogenesis in atherosclerosis, therapeutic strategies targeting angiogenesis must be approached with caution. Strategies aimed at enhancing angiogenesis could be beneficial in promoting collateral circulation and healing in ischemic tissues. However, promoting angiogenesis within atherosclerotic plaques could inadvertently increase the risk of plaque rupture and thrombosis [6].

Several clinical studies are exploring the potential of anti-angiogenic therapies to stabilize plaques by inhibiting abnormal blood vessel formation. Conversely, other strategies focus on improving plaque stability by targeting the inflammatory milieu or promoting the formation of mature, stable blood vessels that are less likely to rupture [7]. Understanding the molecular pathways governing angiogenesis in atherosclerosis is essential for developing therapies that can selectively promote beneficial angiogenesis while preventing harmful vessel growth within plaques [8].

Conclusion

Angiogenesis in atherosclerosis is a multifaceted process that serves as a double-edged sword in cardiovascular disease. On one hand, it provides an adaptive response to tissue hypoxia and could be protective in certain contexts, such as restoring blood supply to ischemic regions. On the other hand, it can exacerbate plaque instability, contributing to the progression of the disease and increasing the risk of acute cardiovascular events. As our understanding of the molecular mechanisms underlying angiogenesis in atherosclerosis deepens, it becomes increasingly clear that future therapeutic strategies must carefully balance the benefits and risks of modulating angiogenesis to improve cardiovascular health. By targeting the right pathways, it may be possible to harness the benefits of angiogenesis while minimizing its potential harms in atherosclerosis.

Acknowledgement

None

Conflict of Interest

None

References

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